【作者】 郭颖；

【导师】 隋树建；

【作者基本信息】 山东大学 ， 内科学（心血管病）（专业学位）， 2017， 博士

【摘要】 背景:重度脓毒症及脓毒性休克具有发病率高,起病急、进展快,治疗难度大,治疗费用高等特点,是住院患者常见的死亡原因,特别是对于危重症患者,重度脓毒症及脓毒性休克已成为其主要死因。研究证实,早期、充分的抗感染治疗对于改善脓毒症患者的生存率极为重要。鉴于以上共识,2012年重度脓毒症和脓毒性休克管理指南推荐在脓毒症治疗初期未获得病原学检查之前,尽早应用广谱、强效的抗生素,以尽量覆盖所有可能引起感染的致病菌,迅速控制感染,即采用"一步到位,重锤猛击"的抗生素应用原则,尽量保证抗感染治疗的最佳疗效。然而,近年来广谱抗生素的过度使用也带来一系列弊端,诸如耐药菌株不断出现,药物不良反应增加等。为了更加合理、有效的应用抗生素,2012年重度脓毒症和脓毒性休克管理指南提出了抗生素降阶梯治疗的概念,即在治疗重度感染的初始阶段选用强效的广谱抗生素,以尽可能的覆盖所有可能的病原菌,迅速控制感染,而在用药48～72 h后,应根据细菌学监测结果及药物敏感性试验,及时换用针对性较强的窄谱抗生素以避免因细菌耐药而造成抗菌药物反复调换或多种联合用药的不良反应。降阶梯治疗从理论层面理解是正确的,但目前其在临床工作中的具体实施尚存在诸多亟待解决的问题。降阶梯治疗何时实施较为适宜?抗生素种类如何选择?对患者预后有哪些影响?对于不同感染来源的重度脓毒症及脓毒性休克患者来说,降阶梯治疗方案有无区别?与之对应的是,抗生素降阶梯治疗仅在35-45%的病例中得到应用。近年来也有较多研究对重度脓毒症和脓毒性休克患者抗生素降阶梯治疗的临床疗效及安全性进行评估,然而其研究结果并不一致。目前,降阶梯治疗是否安全有效尚无十分充分、确切的证据,这其中最关键的问题是缺乏有说服力的随机对照试验。然而,鉴于重度脓毒症和脓毒性休克患者的具体情况(病情重、基线情况复杂等),随机对照试验实现难度很大,且可能存在伦理方面的诸多问题。在这种情况下,Meta分析不失为解决问题的一种方案。Meta分析是循证医学的重要工具,可以提供循证级别较高的证据,受到临床医师、指南制定者以及卫生决策部门的青睐。通过确定合适的纳入和排除标准,恰当的对所纳入文献进行严格的质量评价,并选择正确的统计学方法,可以得出相对客观且可靠的结论。目的:通过纳入所有可及的对照研究进行meta分析,以评估抗生素降阶梯治疗对重度脓毒症及脓毒性休克患者临床结局的影响,从而为临床实践提供更为充分、确切的证据。对象和方法:我们系统检索了 PubMed,EMBASE,Web of Science,CENTRAL on The Cochrane Library数据库。检索关键词是"脓毒症",脓毒性休克"以及"降阶梯治疗",末次检索日期为2015年12月7日。对文献所使用的语言及发表的日期不予限制,所纳入文献的参考文献目录也都经过仔细浏览,以确定是否还有其他符合条件的文献。文献纳入标准为:(1)研究对象为需要经验性抗生素治疗的重度脓毒症和/或脓毒性休克的成人患者(年龄≥18岁)。根据目前的指南,脓毒症被定义为由于微生物或其他病原体侵入人体而导致的一种全身性的、有害的宿主针对感染的全身炎症反应。其中重度脓毒症指脓毒症伴有器官功能障碍或组织灌注不良;脓毒性休克指经充分液体复苏后仍持续低血压的重度脓毒症患者。(2)干预及对比:持续经验性广谱抗生素治疗及抗生素降阶梯治疗。抗生素降阶梯治疗定义为:停用一种抗生素或者抗生素抗菌谱缩窄。(3)观察结果:随访结束时患者的病死率。(4)研究:所有的比较研究,包括观察性研究和临床随机对照研究。本研究应用相对危险度(RR)及95%可信区间来评估降阶梯治疗对于病死率等临床结局的影响。所有的统计分析均应用统计软件Stata 12.0(StataCorp LP,College Station,TX,USA)完成。结果:研究共纳入9篇文献,包含1873个病人。相比较于持续经验性广谱抗生素治疗的患者,降阶梯治疗患者的病死率倾向于更低,但并无显著的统计学差异(RR=0.74,95%CI 0.54-1.03,p=0.005,I2=63.8%)。在亚组分析中,我们纳入了 4项纽卡斯尔-渥太华质量评分较高(7-9分)的研究,发现降阶梯治疗组患者与经验性广谱抗感染治疗组患者病死率仍无明显统计学差异,但结果无明显异质性(RR= 0.85,95%CI 0.67-1.08,p= 0.373,I2 =3.9%)。对于 5 项前瞻性研究来讲,我们也得到了类似结果(RR= 0.91,95%CI 0.75-1.12,p= 0.651,I2 =0.00%)。本研究通过Meta分析所合并的降阶梯治疗患者所占比例为39.5%(95%CI 0.293-0.497,p =0.000,I2= 95.2%)。同时,我们的研究针对3项在西方国家进行的、纳入重度脓毒症和/或脓毒性休克一般患者的研究进行亚组分析,发现降阶梯治疗患者所占比例为 37.1%(95%CI 0.330-0.413,p =0.156,I2=46.20%),同时,该亚组结果异质性不明显。结论:我们的研究表明,在重度脓毒症和/或脓毒性休克患者中,相比于持续经验性广谱抗生素治疗,降阶梯治疗并不影响病死率等临床结局,但是考虑到抗生素降阶梯治疗可以有效避免抗生素滥用、减少细菌耐药、降低住院花费等实际问题,在临床工作中不失为一项明智的选择。同时,鉴于该类患者复杂的临床情况及各地区之间的差异,尚有诸多问题有待进一步探索。设计严密的随机对照研究或两组基线情况匹配良好的观察性研究仍是目前较为迫切的需求。更多还原

【Abstract】 Background:Severe sepsis and septic shock are common causes of mortality in hospital,especially in critically ill patients.Early,adequate antimicrobial therapy targeting at the most likely pathogens before microbiological information is available(broad-spectrum empirical antibiotics therapy)has been shown as extremely important measure to reduce the mortality rates.Empirical antibiotics therapy is also recommended by international guidelines for management of severe sepsis and septic shock in 2012.However,broad-spectrum antibiotics therapy is not without its drawbacks,the risk of leading to overuse of antibiotics and an increase in antimicrobial resistance make it great demand to develop options that are more rational.Antibiotics de-escalation therapy,a strategy in which broad-spectrum empirical antibiotics therapy is started initially but the spectrum is narrowed or an antibiotic is eliminated as soon as microbiological results are available,has been proved to minimize the emergence of drug-resistant organisms and therapy costs during the treatment of patients with severe sepsis and/or septic shock by numerous studies.The strategy termed as "de-escalation therapy" appears theoretically correct.However,a number of crucial elements are unknown and definitely confound de-escalation practice.What was the time period of de-escalation and does it make a difference?Were any algorithms used for broad-spectrum empiric antibiotics choices and were antibiotics correctly chosen as this affects outcomes?What was the source of severe sepsis/septic shock?Correspondingly,de-escalation therapy was realized in approximately 35-45%of the cases.Meanwhile,the current evidence available is not consistent.Some studies concluded that de-escalation was a protective factor for mortality,while others have shown that de-escalation did not affect the mortality,even increased the number of antibiotic days and the risk of superinfection.Because of the lack of sufficiently powered randomized controlled trials(RCTs),the absence of adequate evidence for the efficacy of de-escalation of broad-spectrum empiric antibiotics therapy for patients with severe sepsis and/or septic shock make it hard to draw firm conclusions.Considering the concrete condition of these critically ill patients with severe sepsis and/or septic shock,high-quality randomized controlled trials are hard to come true.A meta-analysis is a feasible way to provide relatively high-grade evidence.Meta-analysis is an important tool of evidence-based medicine,which can provide evidence of higher level and is favored by clinicians,guidelines makers and Health decision-making department.Also,meta-analysis included non-randomized controlled studies plays more and more important role in evidence supports.It is possible to obtain a relatively objective and reliable conclusion by determining the appropriate inclusion and exclusion criteria,properly evaluating quality of the included literature and selecting proper statistical methods.Aim:We performed a meta-analysis of available comparative studies to evaluate the impact of de-escalation therapy on clinical outcomes in adult patients with severe sepsis and/or septic shock.Methods:We performed a systematic literature search in PubMed,EMBASE,Web of Science,and CENTRAL on The Cochrane Library without time or language limitation.The search terms used were "sepsis," "septic shock" and "de-escalation."The inclusion criteria were:(1)Participants:adult patients(age≥18 years)which were diagnosed as severe sepsis and/or septic shock and demanded empiric antibiotics therapy.According to current guidelines,severe sepsis was defined as the presence of infection with systemic manifestations and sepsis-induced organ failure or tissue hypoperfusion;septic shock was defined as severe sepsis with hypotension which cannot be reversed by fluid resuscitation".(2)Interventions and comparisons:continuation of broad-spectrum empiric antibiotics therapy and de-escalation therapy.De-escalation was defined as eliminating of an antibiotics or narrowing the spectrum of antibiotic therapy.(3)Outcomes:the mortality when follow-up ends.(4)Study:any comparative studies,including observational studies and randomized clinical trials.The relative risk(RR)with 95%confidence intervals(CI)was used to evaluate the impact of de-escalation therapy on mortality rate.All statistical analyses were performed by using the statistical software Stata 12.0(StataCorp LP,College Station,TX,USA).Results:Our meta-analysis included nine individual studies,comprising a total of 1873 patients.The mortality trended lower in de-escalation group than in the continuation of broad-spectrum antibiotics group,however,there was no significant statistical difference(RR=0.74,95%CI 0.54-1.03,p=0.005,12=63.8%).When picking out four studies with high methodological quality(NOS score ≧ 7 points),we found no significant statistical difference in mortality between the de-escalation group and the continuation group without significant heterogeneity(RR=0.85,95%CI 0.67-1.08,p=0.373,I2=3.9%).Then we picked out five prospective studies and got a similar conclusion(RR=0.91,95%CI 0.75-1.12,p=0.651,I2=0.0%).The pooled de-escalation rate in observational studies was 39.5%(95%CI 0.293-0.497,p=0.000,I2=95.2%).When we selected the three studies enrolling general patients with severe sepsis and/or septic shock which were performed in Western populations,the pooled de-escalation rate was 37.1%without significant heterogeneity(95%CI 0.330-0.413,p=0.156,I2=46.2%).Conclusion:Our meta-analysis concluded that antibiotic de-escalation therapy has no detrimental impact on mortality in patients with severe sepsis and/or septic shock,as compared to the continuation of broad-spectrum antibiotics.Since de-escalation affords an opportunity to limit overuse of broad-spectrum antibiotics,it should be considered as an advisable option in clinical practice.However,research in this regard has not been accomplished.Well-designed RCTs or better-matched observational studies focusing on other important clinical outcomes are still pressing needs in the near future.更多还原